The research described in this R21 proposal is designed to explore, for the first time, in the intact unanesthetized animal preparation, the prevalence, magnitude, and neurotransmitter basis of putative active sleep-related presynaptic inhibition impinging on individual lumbar sensory tract neurons. We propose to directly test the long-standing hypothesis that the excitability of lumbar sensory neurons is inhibited presynaptically by supraspinal influences during the state of active REM sleep resulting in primary afferent depolarization (PAD) that is mediated by the neurotransmitter GABA. By unique experimental design, we also expect the results obtained from this unique project to conclusively establish whether presynaptic inhibition is either a functional physiological mechanism specific to sensory tract and/or motor neurons during active REM sleep. This will be accomplished by developing procedures to examine for the first time the terminal excitability of individual Ia afferent fiber terminals that not only terminate in L3 Clarke's nucleus, origin of the dorsal spinocerebellar tract (DSCT), but also those branches of the same afferents that terminate in the lower lumbar L6 motor pools. The proposed studies are highly exploratory in nature because they address fundamental questions in basic neuroscience that have eluded direct analyses due to inherent technical difficulties and therefore require novel experimental approaches. The high risk elements associated with this proposal are the technical issues pertaining to direct testing of terminal excitability of identified Ia afferent fibers projecting to Clarke's nucleus, DSCT neurons, and lower lumbar motor pools in the spinal cord of intact, chronic, and behaving animals. If presynaptic PAD mechanisms operate to inhibit the transfer of afferent information to sensory DSCT neurons during active sleep, then quintessential basic knowledge will be added to the fields of spinal cord sensory physiology, pharmacology, and basic sleep research. Such a finding would not only confirm predictions made from seminal studies regarding the existence of active sleep-related presynaptic inhibition, but would also provide a rational basis for future mechanistic investigations aimed at delineating the interneuronal pathways. In contrast, if active sleep related presynaptic inhibition is not demonstrable in the unanesthetized animal, then the phenomenon of presynaptic inhibition of ascending information per se will need re-evaluation vis a vis current views on the brainstem control of spinal cord signal processing. Ultimately, these new procedures and data may provide unique targeting opportunities in the development of new analgesics directed toward various neuropathic pain syndromes.